Abstract
The ability of CD8+ T cells derived from human immunodeficiency virus (HIV)–infected patients to produce soluble HIV–suppressive factor(s) (HIV–SF)1–3 has been suggested as an important mechanism of control of HIV infection in vivo4,5. The C–C chemokines RANTES, MlP–lα and MIP–lβ were recently identified as the major components of the HIV–SF produced by both immortalized and primary patient CD8+ T cells. Whereas they potently inhibit infection by primary and macrophage–tropic HIV–1 isolates, T–cell line–adapted viral strains tend to be insensitive to their suppressive effects6. Consistent with this discrepancy, two distinct chemokine receptors, namely, CXCR4 (ref. 7) and CCR5 (ref. 8), were recently identified as potential co–receptors for T–cell line–adapted and macrophage–tropic HIV–1 isolates, respectively9–12. Here, we demonstrate that the third hypervariable domain of the gp120 envelope glycoprotein is a critical determinant of the susceptibility of HIV–1 to chemokines. Moreover, we show that RANTES, MIP–1α and MIP–1β block the entry of HIV–1 into cells and that their antiviral activity is independent of pertussis toxin–sensitive signal transduction pathways mediated by chemokine receptors. The ability of the chemokines to block the early steps of HIV infection could be exploited to develop novel therapeutic approaches for AIDS.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Walker, C.M., Moody, D., Stites, D.P. & Levy, J.A. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 234, 1563–1566 (1986).
Walker, C.M. & Levy, J.A. A diffusible lymphokine produced by CD8+ T lymphocytes suppresses HIV replication. Immunology 66, 628–630 (1989).
Brinchmann, J.E., Gaudernack, G. & Vartdal, F. CD8+ T cells inhibit HIV replication in naturally infected CD4+ T cells: Evidence for a soluble inhibitor. J. Immunol. 144, 2961–2966 (1990).
Mackewicz, C.E., Ortega, H.W. & Levy, J.A. CD8+ cell anti-HIV activity correlates with the clinical state of the infected individual. J. Clin. Invest. 87, 1462–1466 (1991).
Gomez, A.M., Smaill, P.M. & Rosenthal, K.L. Inhibition of HIV replication by CD8+ T cells correlates with CD4 counts and clinical stage of disease. Clin. Exp Immunol. 97, 68–75 (1994).
Cocchi, F. et al. Identification of RANTES, MIP-lα and MIP-1β as the major HIV-suppressive factors produced by CD8+ T cells. Science 270, 1811–1815 (1995).
Loetscher, M. et al. Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. J. Biol. Chem. 269, 232–237 (1994).
Samson, M., Labbé, O., Molereau, C., Vassart, G. & Parmentier, M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry 35, 3362–3367 (1996).
Feng, Y., Broder, C.C., Kennedy, P.E. & Berger, E.A. HIV-1 entry cofactor: Functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872–877 (1996).
Deng, H.K. et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661–666 (1996).
Dragic, T. et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor C-C CKR-5. Nature 381, 667–673 (1996).
Alkhatib, G. et al. CC CKR5: A RANTES, MIP-lα, MIP-1β receptor as a fusion co-factor for macrophage-tropic HIV-1. Science 272, 1955–1958 (1996).
Gartner, S. et al. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233, 215–219 (1986).
Popovic, M., Sarngadharan, M.G., Read, E. & Gallo, R.C., Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 224, 497–500 (1984).
Lusso, P. et al. Growth of macrophage-tropic and primary human immunodeficiency virus type 1 (HIV-1) isolates in a unique CD4+ T-cell clone (PM1): Failure to downregulate CD4 and to interfere with cell-line-tropic HIV-1. J. Virol. 69, 3712–3720 (1995).
Murphy, P.M. The molecular biology of leukocyte chemoattractant receptors. Annu. Rev. Immunol. 12, 593–633 (1994).
Simon, M.I., Strathmann, M.P. & Gautan, N. Diversity of G proteins in signal transduction. Science 252, 802–807 (1991).
Palker, T.J. et al. Type-specific neutralization of the human immunodeficiency virus with antibodies to envencoded synthetic peptides. Proc. Natl. Acad. Sci. USA 85, 1932–1936 (1988).
Rusche, J.R. et al. Antibodies that inhibit fusion of human immunodeficiency virus-infected cells bind a 24-amino acid sequence of the viral envelope, gp120. Proc. Natl. Acad. Sci. USA 85, 3198–3202 (1988).
Javaherian, K.A. et al. Principal neutralizing domain of the human immunodeficiency virus type 1 envelope protein. Proc. Natl. Acad. Sci. USA 86, 6768–6772 (1989).
Freed, E.O., Myers, D.J. & Risser, R. Identification of the principal neutralizing determinant of human immunodeficiency virus type 1 as a fusion domain. J. Virol. 65, 190–194 (1991).
Shioda, T., Levy, J.A. & Cheng-Meyer, C. Macrophage and T cell-line tropisms of HIV-1 are determined by specific regions of the envelope gp120 gene. Nature 349, 167–169 (1991).
Takeuchi, Y., Akutsu, M., Murayama, K., Shimizu, N. & Hoshino, H. Host range mutant of human immunodeficiency virus type 1: Modification of cell tropism by a single point mutation at the neutralization epitope in the env gene. J. Virol. 65, 1710–1718 (1991).
Chesebro, B., Wehrly, K., Nishio, J. & Ferryman, S. Macrophage-tropic human immunodeficiency virus isolates from different patients exhibit unusual V3 envelope sequence homogeneity in comparison with T-cell-tropic isolates: Definition of critical amino acids involved in cell tropism. J. Virol. 66, 6547–6554 (1992).
Hwang, S.S., Boyle, T.J., Lyerly, H.K. & Cullen, B.R. Identification of envelope V3 loop as the major determinant of CD4 neutralization sensitivity of HIV-1. Science 257, 535–537 (1992).
Ivanoff, L.A. et al. V3 loop region of the HIV-1 gp120 envelope protein is essential for virus infectivity. Virology 187, 423–432 (1992).
Paxton, W.A. et al. Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remained uninfected despite multiple high-risk sexual exposure. Nature Med. 2, 412–417 (1996).
Bacon, K.A., Premack, B.A., Gardner, P., Schall, T.J. Activation of dual T cell signaling pathways by the chemokine RANTES. Science 269, 1727–1730 (1995).
Koito, A., Harrowe, G., Levy, J.A. & Cheng-Mayer, C. Functional role of the V1/V2 region of human immunodeficiency virus type 1 envelope glycoprotein gp120 in infection of primary macrophages and soluble CD4 neutralization. J. Virol. 68, 2253–2259 (1994).
Willey, R.L. & Martin, M.A. Association of human immunodeficiency virus type 1 envelope glycoprotein with particles depends on interactions between the third variable and conserved regions of gp120. J. Virol. 67, 3639–3643 (1993).
Stamatatos, L., Werner, A. & Cheng-Mayer, C. Differential regulation of cellular tropism and sensitivity to soluble CD4 neutralization by the envelope gp120 of human immunodeficiency virus type 1. J. Virol. 68, 4973–4979 (1994).
Carrillo, A. & Ratner, L. Human immunodeficiency virus type 1 tropism for T-lymphoid cell lines: role of the V3 loop and C4 envelope determinants. J. Virol. 70, 1301–1309 (1996).
Gao, W.-Y., Cara, A., Gallo, R.C. & Lori, F. Low levels of deoxynucleotides in peripheral blood lymphocytes: a strategy to inhibit human immunodeficiency virus replication. Proc. Natl. Acad. Sci. USA 90, 8925–8928 (1993).
Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual, edn. 2 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Cocchi, F., DeVico, A., Garzino-Demo, A. et al. The V3 domain of the HIV–1 gp120 envelope glycoprotein is critical for chemokine–mediated blockade of infection. Nat Med 2, 1244–1247 (1996). https://doi.org/10.1038/nm1196-1244
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm1196-1244
This article is cited by
-
Co-receptor signaling in the pathogenesis of neuroHIV
Retrovirology (2021)
-
A systematic analysis of intrinsic regulators for HIV-1 R5 to X4 phenotypic switch
Quantitative Biology (2017)
-
Antigenic and 3D structural characterization of soluble X4 and hybrid X4-R5 HIV-1 Env trimers
Retrovirology (2014)
-
Platelets: at the nexus of antimicrobial defence
Nature Reviews Microbiology (2014)
-
Genetic diversity of the highly variable V1 region interferes with Human Immunodeficiency Virus type 1 envelope functionality
Retrovirology (2013)